This invention relates to a procedure and compounds for non-invasive imaging and diagnosis of upper gastrointestinal ulcers.
It is estimated that up to 10% of the population of the United States has upper gastrointestinal ulcer disease. Many of these patients will undergo either endoscopy or upper gastrointestinal X-ray examination. Additionally, many patients who do not have ulcer disease undergo these examinations in order to rule out such disease.
Upper gastrointestinal X-ray examination is currently the most common means for diagnosing ulcers. Images are taken after the patient swallows barium fluid. An ulcer will be revealed in profile as an indentation in the lining of the stomach or duodenum. However, failure to see an ulcer does not exclude it due to the high false negative rate for X-ray detection of duodenal ulcers. Applied Radiology, 20, 120 (May/June 1982).
One of the major drawbacks of X-ray/barium diagnostic techniques for upper gastrointestinal ulcers is the relatively poor resolution that can be obtained. Such X-ray techniques have about a 50% success rate in detecting 10 mm ulcers. In other words, smaller ulcers are virtually always missed in an X-ray diagnosis. However, as any gastroenterologist can certify, there is no rigid correlation between ulcer size and patient discomfort. The failure of X-ray techniques to visualize and diagnose relatively small ulcers is a serious drawback to that technique. Moreover, X-ray techniques necessarily entail exposure to a significant amount of ionizing radiation. The exposure problem is exacerbated by the fact that multiple exposures from different angles are required. The radiation exposure is typically 1000-2000 millirems/hr.
Endoscopy frequently reveals ulcers not seen by X-ray examination. Looking through a fiberoptic instrument, the physcian can light up the walls of the stomach and duodenum to visualize the ulcers. Endoscopy is associated with occasional complications. Sedation is required. The technique also entails the risk of serious complications such as perforation and aspiration. Harrison's Principles of Internal Medicine 1360 (9th ed. 1980).
Controlled clinical trials have shown that a derivative of colloidal bismuth subcitrate, tripotassium dicitrato bismuthate, marketed as a pharmaceutical in Europe under the trademark "De-Nol", healed duodenal and gastric ulcers significantly better than placebo. Several double-blind controlled clinical trials showed that tripotassium dicitrato bismuthate promoted ulcer healing in patients with chronic gastric or duodenal ulcers. Gastroenterology 82: 864-70 (1982).
We have developed a simple method for labeling colloidal bismuth subcitrate and related compounds with technetium-99m and other radioiostopes. The resulting solution is easily administered orally and imaging may be carried out with standard scintigraphic equipment. Animal studies show that the agent is stable in vivo and has utility for the clinical evaluation of gastrointestinal ulcer disease along with other diseases associated with a loss of mucosal integrity.
Accordingly, it is an object of the present invention to provide an alternative to X-ray/barium techniques and endoscopy for the diagnosis of upper GI ulcers and other disorders characterized by disruption of the gastrointestinal mucosa.
Another object of the present invention is to provide such a diagnostic technique that involves much lower exposure to ionizing radiation than does a complete X-ray series.
Still another object of the present invention is to provide a highly sensitive non-invasive diagnostic technique capable of detecting ulcers significantly smaller than can be resolved with x-ray techniques.
Still another object of the present invention is to provide a diagnostic technique for ulcers that requires relatively inexpensive equipment.
Yet another object of the present invention is to provide novel radiolabeled compounds for use in such a technique.